Varicella-zoster virus (VZV) is the etiologic agent of chickenpox and herpes zoster. We have developed a system to mutate individual genes or to insert foreign DNAs in the VZV genome. These mutant viruses are being assayed for their ability to grow in cell culture or in animals models. Deletion or inactivation of some of these genes (ORF1, ORF8, ORF10, ORF13, ORF14, ORF47, ORF66) results in no discernable difference in the growth of the virus in cell culture, while inactivation of other genes (ORF9A, ORF19) or pairs of genes (ORF 47 and ORF66) reduces the ability of the virus to grow in cell culture. Analysis of VZV mutants has shown that VZV ORF47 and ORF66 have protein kinase activity and that ORF9A is important for syncytia formation of VZV-infected cells. Guinea pigs will be inoculated with selected VZV mutants to determine if the viruses have lost the ability to establish latency or reactivate from the central nervous system. Foreign genes have been inserted into the VZV genome. Intravitreal inoculation of guinea pigs with VZV expressing beta-galactosidase resulted in a chronic uveitis with a mononuclear cell infiltrate in the vitreous of nearly all of the animals that persisted for at least two months. Staining with X-gal demonstrated the presence of VZV in the ciliary body or iris in about 50% of the animals for at least two months after inoculation. Inoculation of guinea pigs with VZV expressing herpes simplex virus glycoprotein D, followed by challenging the animals with intravaginal herpes simplex virus, resulted in reduced severity of genital herpes.